Novel endogenous 1,2,3,4-tetrahydroisoquinoline derivatives: uptake by dopamine transporter and activity to induce parkinsonism.
We designed as candidate metabolites and synthesized two 1-benzyl-1,2,3,4-tetrahydroisoquinoline derivatives containing a dopamine moiety: 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4'DHBnTIQ) and 1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (6,7DHBnTIQ). Both were detected in mouse brain as endogenous amines by gas chromatography/mass spectrometry. 3',4'DHBnTIQ induced parkinsonism in mice when chronically administered intraperitoneally, whereas 6,7DHBnTIQ did not despite the structural similarity of the two compounds. This difference may be related to cellular uptake: In rat striatal synaptosomes, these compounds were intracellularly transported by the dopamine transporter with Km values of 6.14 and 7.82 microM and Vmax values of 214.3 and 112.2 pmol/min/mg of protein, respectively. Thus, endogenous 3',4'DHBnTIQ may be actively transported into dopaminergic neurons and accumulated there, contributing at least in part to the induction of idiopathic Parkinson's disease.
Kawai
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Makino
Y
Y
Hirobe
M
M
Ohta
S
S
D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009498:Neurotoxins / Q000493:pharmacokinetics* / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000378:metabolism; D014213:Tretoquinol / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity
C110419:1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline; C102873:1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D014213:Tretoquinol; D004298:Dopamine